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In critically ill patients, overweight and obesity are associated with acute respiratory distress syndrome and acute kidney injury (AKI). Although obesity is known to increase oxidative stress, worsen inflammation, and induce a state of Klotho deficiency, its effect on ischemia–reperfusion injury (IRI)-induced AKI is unknown. We hypothesized that obesity would aggravate renal IRI in mice. We fed mice a standard or high-fat diet for eight weeks. The mice were divided into four groups and submitted to sham surgery or IRI: obese, normal, normal + IRI, obese, and obese + IRI. All studies were performed 48 h after the procedures. Body weights were higher in the obese and obese + IRI groups than in the normal and normal + IRI groups, respectively. Serum glucose and cholesterol did not differ among the groups. Creatinine clearance also did not differ among the groups. Survival and urinary osmolality were lower in the obese + IRI group than in the normal + IRI group, whereas urinary neutrophil gelatinase-associated lipocalin levels, tubular injury scores, and caspase 3 expression were higher. In the obese + IRI group, the PCNA-positive cell counts were highest, as were the levels of oxidative stress (urinary levels of thiobarbituric acid-reactive substances and renal heme oxygenase-1 protein expression), and renal Klotho protein expression was lowest. Notably, macrophage infiltration was greater in the obese group mice than in the normal group mice, despite the fact that none of those mice were induced to AKI. In conclusion, greater oxidative stress might aggravate IRI in obese individuals, and Klotho could be a therapeutic target in those with AKI.